NAD+ and Ovarian Aging: Can It Help With Menopause?

Key Takeaways

• The ovaries are amongst the first organs to age. Research has associated ovarian aging with declining NAD+ levels.

• NAD+ is a critical coenzyme involved in hundreds of cellular processes. NAD+ levels decrease with age.

• Emerging research suggests boosting NAD+ levels may help slow ovarian aging at a cellular level.

Related Product

• Basis: contains the NAD+ precursor NR and pterostilbene, is clinically proven to increase NAD+ levels by 40%, and has been linked to improvements in specific menopause symptoms. *See disclaimer below.

Did you know the ovary is one of the first organs to age? You might be nodding your head yes if you’re a woman approaching menopause experiencing a lengthy list of symptoms such as hot flashes, irregular periods, and sleep disturbances, which all stem from the age-related decline in ovarian function. In fact, the ovary ages roughly 2.5 times faster than the rest of your body. The dip in ovarian reserve and reduced egg quality starts as early as your late 30s and continues until your menstrual cycle ends with menopause. Menopause is the final step of ovarian aging.

Ovarian aging contributes to infertility and a loss of endocrine function. Because of this rapid decline and the important role hormones play in our overall health, this means women experience an erratic decline in the health and function of their other organs, in contrast to men who experience a more gradual decline. In fact, research shows that hormonal changes associated with menopause accelerate biological aging in the rest of the body by 6%. Previously regarded as reproductive organs, the ovaries are now thought of as “architects of health in female bodies.” Ovarian aging is associated with a decrease in ovarian levels of NAD+ (nicotinamide adenine dinucleotide), a vital coenzyme present in every living cell. And preclinical studies in mice suggest that increasing NAD+ levels may help delay ovarian aging. So, what’s the connection between NAD+ and ovarian aging? We’ll explain.

NAD+ and hormone production

In females of reproductive age, estradiol is the major circulating estrogen. Estradiol is essential to skeletal, vascular and energy homeostasis in women. During the menopause transition, estradiol levels plummet and estrone (a weaker form of estrogen) dominates. Estrone becomes the main source of generating estradiol after menopause [1]. The reduced levels of estradiol in post-menopausal women can lead to osteoporosis [2], increased risk of cardiovascular disease [3] and increased risk of type 2 diabetes [4].

NADPH, which is the reduced form of NADP, is a cofactor for enzymes responsible for the synthesis of most steroid derived hormones, including estrone and estradiol. Specifically, an enzyme called 17-b hydroxysteroid dehydrogenase (17b-HSD) uses NADPH to catalyze the conversion of estrone to estradiol [5]. NAD+ is a precursor molecule for NADPH (meaning it can get converted to NADPH) and both NAD+ and NADPH levels decline with age [6,7]. 

NAD+ and ovarian cell health 

NAD+ is not only important for hormone production. The abundance of this molecule is associated with a healthy aging status [8]. NAD+ is estimated to be involved in over 500 different cellular reactions in humans, including those in the ovaries. It plays a crucial role in cellular energy production, mitochondrial function, combatting oxidative stress, and DNA maintenance—declining mitochondrial health, oxidative stress, and DNA damage are key factors in ovarian aging [9]. NAD+ is especially in high demand during ovulation; it’s needed for follicle rupture, egg release, and corpus luteum formation, which helps sustain the embryo in early pregnancy [10]. 

Loss of ovarian NAD+

A cross-section of an adult mouse ovary showing the presence of the NAD-consuming enzyme CD38 (red signal). Nuclei are shown in blue. Image courtesy of the Verdin Lab, Buck Institute

While NAD+ levels decline throughout our body with age, preclinical studies suggest that the ovaries experience an earlier onset of this decline [11]. A growing number of studies point to an enzyme called CD38, an NAD-consuming enzyme, whose expression increases in the ovaries with age [10,11]. In these studies, reducing the level of CD38 increased NAD+ levels and mitigated ovarian aging, preserving fertility and follicle reserve in mice, while increasing CD38 levels had the opposite effects. 

Restoring NAD+ levels

Supplementing aged mice with NMN, an NAD+ precursor molecule, has been shown to increase NAD+ levels in the oocytes and improve oocyte quality, ovulation rate, and fertility [12]. The study also suggests that SIRT2, a member of the sirtuin family of enzymes, may be mediating this improvement. Sirtuins are a family of seven proteins that are essential for healthy aging. They play a critical role in cell metabolism and gene expression and are often referred to as “the guardians of the genome.” Importantly, sirtuins can only function in the presence of NAD+. As NAD+ levels decline with age, so does the activity of sirtuins. 

In another mouse study, supplementation with NR, another NAD+ precursor molecule, also resulted in increased ovarian NAD+ levels, ovulatory potential, and oocyte quantity and quality. NR supplementation also improved ovarian mitochondrial functions [13].

These studies were carried in mice and have yet to be reproduced in humans. However, a recent open-label, survey-based study (ClinicalTrials.gov identifier NCT04841499) demonstrated that women experiencing pre/post-menopausal symptoms (aged 35 years and older) saw a significant improvement in undesirable menopausal symptoms after supplementing with Basis (Holmes HE, et al., manuscript in preparation). Basis contains NR (one of the NAD+ precursors mentioned above) and pterostilbene (a sirtuin 1 activator) and is clinically proven to increase NAD+ levels in the blood by ~40%. After 7 days of supplementation with Basis, 78% of the women reported significant decreases in both the frequency and magnitude of bloating, 75% reported an improvement in the frequency of hot flashes, 84% reported an improvement in the frequency of poor sleep, and 91% reported an improvement in the unpleasantness of poor sleep.* This improvement in symptoms was accompanied by a significant increase in their estradiol/estrone ratio. Women who were not experiencing any symptoms associated with menopause, did not report any significant changes.

While more research is needed to fully understand the role of NAD+ in ovarian aging, it’s clear that this molecule is vital for supporting healthy aging at a cellular level, across various types of tissues and organs.

Disclaimer:

*Based on self-reported changes in symptoms before/after Basis supplementation in 32 women experiencing pre/postmenopausal symptoms. Changes in these symptoms can be attributable to other factors unrelated to Basis, such as diet, physical activity, and lifestyle choices.

References:

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12. Bertoldo MJ, Listijono DR, Ho WJ, et al. NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Rep. 2020;30(6):1670-1681.e7. 
13. Yang Q, Cong L, Wang Y, et al. Increasing ovarian NAD+ levels improve mitochondrial functions and reverse ovarian aging Free Radic Biol Med. 2020;156:1-10.